Earlier studies showed that IA-2 and IA-2beta are enzymatically inactive members of the protein tyrosine phosphatase family, widely distributed in neuroendocrine cells throughout the body and transmembrane components of DCV. Further studies showed that IA-2/IA-2beta belong to an ancient gene family going back 500 million years with homologs in Drosophila and C. elegans. Studies over the last several years, in mice, showed that IA-2 and IA-2beta, which influence the secretion of hormones, also modulate the secretion of neurotransmitters in the brain. These observations led to the discovery that the knockout of both IA-2 and IA-2beta resulted in profound changes in behavior and learning. Measurement of neurotransmitters revealed that norepinephrine, dopamine and serotonin were significantly decreased in the brain of double knockout (DKO) mice (P<0.05 to <0.001). In a variety of tests, DKO mice showed a highly significant increase in anxiety-like behavior (P<0.01 to <0.001) and impairment of conditioned learning (P<0.01) as compared to WT mice. GABA and glutamate from synaptosomes of DKO mice also was significantly decreased (P<0.01). Additional studies revealed that the knockout of both IA-2 and IA-2beta also had a profound effect on the circadian rhythm of blood pressure, heart rate, body temperature and physical activity as evaluated by radio-telemetry with probes placed in the aortic arch. Electrophysiology studies showed loss of rhythmicity in the suprachiasmatic nuclei, the site of the brains master circadian oscillator, pointing to the importance of neurotransmitters in regulating circadian oscillations. Taken together these studies show that IA-2 and IA-2beta are important molecules in modulating neuroendocrine secretion and raise the possibility that at the human level alterations in other structural proteins of DCV also might result in a decrease in the secretion of hormones and neurotransmitters and this, in turn, could lead to a variety of physiologic and behavioral dysfunctions (e.g., affective disorders). Over the last year we have focused on 1) the cell biology of IA-2 and IA-2beta, 2) the effect of these two proteins on learning and 3) have continued our studies on autoantibodies and polyreactive antibodies.